Clinical Trials

Modafinil, trade named Provigil, is a medication approved by the Food and Drug Administration
for the treatment of narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work
sleep disorder. Each of these problems is characterized by difficulty sleeping at night and
excessive daytime sleepiness. Modafinil is prescribed during the day to counteract this
sleepiness. The idea behind this treatment is that sleepiness that leads to napping during
the day prevents a patient from being tired or sleepy enough to get good sleep at night. This
study is designed to determine if the medication can "reset" participants' sleep/wake rhythm
to a more normal rhythm.

Stanford is currently not accepting patients for this trial.For more information, please contact Ban Ku, (650) 849 - 1971.

Abstract

To compare the outcome of donepezil treatment in ethnically diverse Alzheimer disease (AD) patients with ethnically diverse AD patients who did not receive donepezil.Patients meeting NINCDS-ADRA criteria for probable or possible AD from a consortium of California sites were systematically followed for at least 1 year in this prospective, observational study. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria. Patients self-identified their ethnicity.The 64 ethnically diverse AD patients who completed the study and received donepezil treatment had an average 1-year decline of 2.30 points (standard deviation: 3.9) on the 30-point Mini-Mental State Exam compared with a 1.70-point (standard deviation: 4.2) decline in the 74 ethnically diverse completers who received no donepezil or other anti-AD drugs during the study period. This difference was not statistically significant. The overall Cohen effect size of this treatment-associated difference was estimated at -0.15. After using propensity analyses and other techniques to assess factors that could bias prescribing decisions, the lack of benefits associated with donepezil treatment remained. The lack of donepezil benefits also remained when more traditional analyses were applied to these data.Ethnically diverse AD patients in this study apparently did not benefit from 1 year of donepezil treatment. These unpromising results are in contrast to modest benefits of donepezil treatment measured in a directly comparable California study involving white non-Latino AD patients.

Abstract

Alzheimer's disease (AD) shortens life-expectancy, but the effects of pharmacological treatments for this disorder on mortality have not been studied. We compared two commonly prescribed medications, donepezil and memantine, with respect to the length of survival of veterans presumed to have AD. The Computerized Medical Records System at the Veterans Affairs Palo Alto Health Care System (VAPAHCS) was used to identify all patients prescribed these medications between 1997 and 2008. The VAPAHCS approved donepezil in 1997 and memantine in 2004. Kaplan-Meier and Cox regression analyses were used to test for chronological and drug-related associations with survival in 2,083 male veterans aged 55 years and older receiving prescriptions for donepezil, memantine, or both. Overall patient mortality decreased in the 2004 to 2008 era, compared with the 1997 to 2003 era, pre-memantine (HR: 0.75; 95% CI: 0.63, 0.89; p = 0.001). In analyses confined to the 2004 to 2008 era, patients prescribed memantine alone survived significantly longer (median survival 8.9 years) than those prescribed donepezil alone (HR: 2.24; 95% CI: 1.53, 3.28; p < 0.001) or both donepezil and memantine (HR: 1.83; 95% CI: 1.14, 2.94; p = 0.012). While this study has several limitations, these findings suggest that memantine treatment is associated with an increased life-expectancy relative to donepezil treatment. Additional research is needed to replicate these unexpected findings and identify potential mechanisms to explain this apparent association, to establish if the relationship applies to other cholinesterase inhibitors, and to discover whether the findings generalize to women and patient populations with characteristics different from those of the veterans in this study.

Abstract

AD is a public health epidemic, which seriously impacts cognition, mood and daily activities; however, one type of activity, exercise, has been shown to alter these states. Accordingly, we sought to investigate the relationship between exercise and mood, in early-stage AD patients (N=104) from California, over a 1-year period. Patients completed the Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), and Blessed-Roth Dementia Rating Scale (BRDRS), while their caregivers completed the Yale Physical Activity Survey (YALE), Profile of Mood States (POMS), the Neuropsychiatric Inventory (NPI) and Functional Abilities Questionnaire (FAQ). Approximately half of the participants were female, from a variety of ethnic groups (Caucasian=69.8%; Latino/Hispanic Americans=20.1%). Our results demonstrated that the patients spent little time engaged in physical activity in general, their overall activity levels decreased over time, and this was paired with a change in global cognition (e.g., MMSE total score) and affect/mood (e.g., POMS score). Patients were parsed into Active and Sedentary groups based on their Yale profiles, with Active participants engaged in walking activities, weekly, over 1 year. Here, Sedentary patients had a significant decline in MMSE scores, while the Active patients had an attenuation in global cognitive decline. Importantly, among the Active AD patients, those individuals who engaged in walking for more than 2 h/week had a significant improvement in MMSE scores. Structured clinical trials which seek to increase the amount of time AD patients were engaged in walking activities and evaluate the nature and scope of beneficial effects in the brain are warranted.

Abstract

One of the hypothesized causes of the breakdown in sleep-wake consolidation often occurring in individuals with Alzheimer disease (AD) is the dysfunction of the circadian clock. The goal of this study is to report indices of sleep-wake function collected from individuals with AD in relation to relevant polymorphisms in circadian clock-related genes.One week of ad libitum ambulatory sleep data collection.At-home collection of sleep data and in-laboratory questionnaire.Two cohorts of AD participants. Cohort 1 (N = 124): individuals with probable AD recruited from the Stanford/Veterans Affairs, National Institute on Aging Alzheimer's Disease Core Center (N = 81), and the Memory Disorders Clinic at the University of Nice School of Medicine (N = 43). Cohort 2 (N = 176): individuals with probable AD derived from the Alzheimer's Disease Neuroimaging Initiative data set.Determination of sleep-wake state was obtained by wrist actigraphy data for 7 days in Cohort 1 and by the Neuropsychiatric Inventory questionnaire for Cohort 2. Both cohorts were genotyped by using an Illumina Beadstation (Illumina, San Diego, CA), and 122 circadian-related single-nucleotide polymorphisms (SNPs) were examined. In Cohort 1, an additional polymorphism (variable-number tandem repeat in per3) was also determined.Adjusting for multiple tests, none of the candidate gene SNPs were significantly associated with the amount of wake time after sleep onset (WASO), a marker of sleep consolidation. Although the study was powered sufficiently to identify moderate-sized correlations, we found no relationships likely to be of clinical relevance.It is unlikely that a relationship with a clinically meaningful correlation exists between the circadian rhythm-associated SNPs and WASO in individuals with AD.

Abstract

To determine if results from randomized clinical trials of donepezil in Alzheimer disease (AD) patients can be applied to AD patients in clinical practice by comparing the findings from a Nordic one-year randomized AD donepezil trial with data from a one-year prospective, observational study of AD patients.AD patients from a consortium of California sites were systematically followed for at least one year. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria.The 148 California patients treated with donepezil had a one-year decline of 1.3 (3.5 SD) points on the Mini-Mental State Exam compared to a decline of 3.3 (4.4 SD) in the 158 AD patients who received no anti-Alzheimer drugs. The Mini-Mental State Exam decline in Nordic sample was approximately 0.25 points for the 91 patients receiving donepezil and approximately 2.2 for the 98 placebo patients. The overall effect sizes were estimated at about 0.49 in both studies. The California data were further analyzed using propensity methods; after taking into account differences that could bias prescribing decisions, benefits associated with taking donepezil remained.A comparison of a randomized clinical trial of donepezil in AD patients and this observational study indicates that if appropriate methodological and statistical precautions are undertaken, then results from randomized clinical trials can be predictive with AD patients in clinical practice. This California study supports the modest effectiveness of donepezil in AD patients having clinical characteristics similar to those of the Nordic study.

Abstract

A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2-6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.

Abstract

The aim of this study was to use a signal detection method to examine the prevalence of, and patient characteristics associated with, medication with potential to impair cognition and cholinesterase inhibitor use in patients with Alzheimer's disease.A cross-sectional study was conducted of 1,954 patients with a diagnosis of probable or possible Alzheimer's disease. Concurrent medications were measured, specifically: (1) a medication with potential to impair cognition or (2) a cholinesterase inhibitor. Predictor variables included age, gender, ethnic group, education, age of symptom onset, number of prescriptions, number of medical diagnoses, Mini-Mental State Examination (MMSE), Blessed-Roth Dementia Rating Scale (BRDRS), probable versus possible AD diagnosis.Fifteen percent of the Alzheimer's disease patients were on a medication with potential to impair cognition, and 44% were on a cholinesterase inhibitor. Patient characteristics associated with the prescription of a medication with potential to impair cognition included total number of prescription medications, low education, low MMSE, older age, reported lack of vitamin use, and more medical diagnoses. Patient characteristics associated with the prescription of a cholinesterase inhibitor included reported use of vitamins, the total number of prescription medications, fewer medical diagnoses, lower age of symptom onset, and higher education.Determining the patient characteristics associated with the prescription of a medication with potential to impair cognition can help clinicians identify patients who are at risk for drug-related morbidity. Patient characteristics unassociated with dementia appear to influence the prescription of cholinesterase inhibitors. Signal detection analysis is well suited to this type of research.

Abstract

Clinical researchers often propose (or review committees demand) pilot studies to determine whether a study is worth performing and to guide power calculations. The most likely outcomes are that (1) studies worth performing are aborted and (2) studies that are not aborted are underpowered. There are many excellent reasons for performing pilot studies. The argument herein is not meant to discourage clinical researchers from performing pilot studies (or review committees from requiring them) but simply to caution against their use for the objective of guiding power calculations.

Abstract

The current study used Department of Veteran's Affairs (VA) clinical records, State of California pesticide application records, spatial maps of distribution of Parkinson's disease patients, and pesticide applications to determine if there was evidence for "blow-in" of pesticides as a factor in explaining the prevalence of Central Valley Parkinson's disease. The results did not support the hypothesis of increasing prevalence of Parkinsonism attributable to wind drift.

Abstract

Off-label prescribing of medications, polypharmacy, and other questionable prescribing practices have led investigators to examine a large VA pharmacy database to determine if physician prescribing decisions appear reasonable.The current study addresses the question of physician prescribing of atypical antipsychotics in 34,925 veterans with schizophrenia, using a series of signal detection analyses.These results suggest that only three factors (hospital size, age, and secondary diagnosis) allow classification of patients prescribed atypicals into three groups with frequencies of use of atypicals ranging from 43% to 79%, and that these results are consistent with reasonable clinical practice.Results of two-stage signal detection analyses are readily interpretable by clinicians and administrators who are faced with the task of evaluating how physicians prescribe medications in clinical practice. Physicians' decisions to prescribe atypical antipsychotics are based on both patient and fiscal considerations. This likely reflects a combination of clinical judgment and institutional guidelines.

Abstract

It is largely unknown why some patients with Alzheimer's disease (AD) decline cognitively more rapidly than others. Genetic differences among patients could influence rate of decline. Brain-derived neurotrophic factor (BDNF) is a neurotrophin important in the survival neurons and in memory function. BDNF levels are reduced in the brain in AD. The Val66Met polymorphism in the BDNF gene modifies neuronal BDNF secretion, and affects hippocampal function and memory performance. We tested the hypothesis that the BDNF Val66Met polymorphism influences rate of cognitive decline in AD. In a sample of 149 AD patients followed for an average of 3.9 years, we found no effect of BDNF Val66Met genotype on rate of change in the Mini Mental State Examination. Results were similar when we excluded patients taking an acetylcholinesterase inhibitor, those placed in a nursing home during the study, or those with a neuropathological diagnosis that included AD plus an entity other than AD. We also found no evidence that the effects of the BDNF Val66Met genotype depend on APOE genotype, which itself had no effect on rate of cognitive change. These findings suggest that the functional BDNF Val66Met variant is not a major determinant of rate of cognitive decline in AD.

Abstract

There is paucity of medical literature on the use of lamotrigine in elderly patients who have behavior problems and diverse psychiatric syndromes. This article is a retrospective case series summarizing the authors' experience with this medication. In a 20-patient case series from an institutional review board-approved retrospective chart review, the tolerability and efficacy of lamotrigine was evaluated for the management of agitated and aggressive behaviors in nursing home patients with a range of psychiatric and medical diagnoses. Nineteen of the elderly nursing home patients tolerated lamotrigine treatment, and 18 showed modest clinical improvement. These results support the authors' belief that controlled clinical investigations of this medication should be performed.

Abstract

The objective of this study was to assess the convergent validity of a 26-point Telephone Mini-Mental State Examination (MMSE) in a longitudinal cohort of 46 Alzheimer's disease (AD) patients. Paired in-person and telephone MMSE observations were collected within 35 days of each other. The setting was the Stanford/VA Alzheimer's Center in Palo Alto, California, and patients' residences. The 30-point Folstein MMSE was administered in-person, and a 26-point telephone version of the MMSE, adapted from the Adult Lifestyles and Function Interview (ALFI)-MMSE. Total scores for the in-person and telephone MMSE versions correlated strongly (Pearson's r =.88, P

Abstract

The purpose of this study was to assess whether pharmacy database information from US Department of Veterans Affairs (VA) medical centers could be used to screen for areas of higher Parkinson's disease prevalence in patients exposed to pesticides. The authors used pharmacy data sets and compared the use of antiparkinsonian medications at 2 VA medical centers in California: one in Palo Alto, near the ocean, and one in Fresno, downwind from extensively farmed parts of the Central Valley. They found that patients at Fresno had higher odds ratios (1.5-1.8) for the use of Parkinson's disease medications than patients at Palo Alto. These data are consistent with the observations of prior epidemiologic studies and suggest that VA pharmacy databases can prioritize locations for further epidemiologic research. However, a thorough exploration of alternative explanations is needed to reach definitive conclusions regarding the findings suggested by this method.

Abstract

Disturbed sleep is a major clinical problem in Alzheimer's disease (AD). Apolipoprotein epsilon4 (APOE epsilon4) carrier status may increase risk of AD, yet there are no data on relations between APOE status and progression of sleep disturbance in AD. The objective of this study was to determine if sleep parameters in AD patients change over time as a function of APOE carrier status. Forty-four community-dwelling AD patients with diagnosis of probable AD were followed from early stages of disease. Their sleep/wake parameters were compared according to APOE status. For APOE epsilon4 carriers, only wake after sleep onset (WASO) increased in association with lower cognitive function as indicated by the Mini-Mental State Examination (MMSE); for non-epsilon4 subjects, increases in WASO and declines in total sleep time, sleep efficiency, and the amplitude of the rest/activity circadian rhythm over time were associated with lower performance on the MMSE. In these data, APOE status was associated with the progression of sleep/wake disturbances in AD. Overall, there was greater deterioration on sleep parameters in patients negative for the epsilon4 allele.

Abstract

We used a novel application of a signal detection technique, receiver operator characteristics (ROC), to describe factors entering a physician's decision to switch a patient from a typical high potency neuroleptic to a particular atypical, olanzapine (OLA) or risperidone (RIS).ROC analyses were performed on pharmacy records of 476 VA patients who had been treated on a high potency neuroleptic then changed to either OLA or RIS.Overall 68% patients switched to OLA and 32% to RIS. The best predictor of neuroleptic choice was age at switch, with 78% of patients aged less than 55 years receiving OLA and 51% of those aged greater than or equal to 55 years receiving OLA (chi(2)=38.2, P<0.001). Further analysis of the former group indicated that adding the predictor of one or more inpatient days to age increased the likelihood of an OLA switch from 78% to 85% (chi(2)=7.3, P<0.01) while further analysis of the latter group indicated that adding the predictor of less than 10 inpatients days to age decreased the likelihood of an OLA switch from 51% to 45% (chi(2)=7.0, P<0.01).ROC analyses have the advantage over other analyses, such as regression techniques, insofar as their "cut-points" are readily interpretable, their sequential use forms an intuitive "decision tree" and allows the potential identification of clinically relevant "subgroups". The software used in this analysis is in the public domain (http://mirecc.stanford.edu).

Abstract

Part of the challenge in research on degenerative neurologic disease relates to distinguishing those measurements that essentially describe patient characteristics stable across the course of illness (traits) from those that vary systematically within subjects (states), particularly those specifically related to stage or duration of illness. A components-of-variance approach was used to examine the state versus trait aspects of the Alzheimer's Disease Assessment Scale (ADAS) Cognitive and Noncognitive subscales, a clinical instrument frequently used in research on Alzheimer disease. Subjects were 190 patients with probable AD followed longitudinally. Stage of illness was indexed by mental status scores. Analysis of variance was used to partition total variance into that associated with subjects (trait), stages (state: stage), subjects x stages (state: other), and error. ADAS Cognitive scores were strongly related to stage of illness (83% of true variance). ADAS Noncognitive scores were modestly related to stage (approximately 21% of true variance) and moderately related to state: other (47%). We discuss how state-trait analyses can be helpful in focusing attention on those areas of assessment most likely to accomplish specific objectives.

Abstract

We report a randomized, double-blind, parallel group, placebo-controlled study to test the effects of the acetylcholinesterase inhibitor, donepezil (5 mg/d for 30 days), on aircraft pilot performance in 18 licensed pilots with mean age of 52 years. After 30 days of treatment, the donepezil group showed greater ability to retain the capacity to perform a set of complex simulator tasks than the placebo group, p < 0.05. Donepezil appears to have beneficial effects on retention of training on complex aviation tasks in nondemented older adults.

Abstract

Major advances in understanding the physiology and genetics of circadian rhythm in the past decade challenge the researcher of sleep/wake disorders in Alzheimer's disease (AD) to distinguish patient characteristics stable across the course of illness ("traits") from characteristics that vary with stage of illness ("states"). A components-of-variance approach with a repeated measures model was used to examine the between-subjects variance over time ("trait") vs. within-subjects ("state") variance in 42 patients with probable AD followed, on average, over 2 years on actigraphic sleep/wake measures. Mental status scores indexed stage of illness. Actigraphic measures of sleep efficiency and circadian rhythmicity appeared predominantly "trait," with between-individual differences accounting for over 55% of variance compared to the less than 5% of variance related to stage of cognitive impairment. We discuss how "state-trait" analyses can be helpful in identifying areas of assessment most likely to be fruitful objectives of physiologic and genetic research on sleep/wake disturbance in AD.

Abstract

In the current study of 1062 Alzheimer's disease (AD) patients, we employed receiver operating characteristic curve analysis to identify characteristics of patients at increased risk for rapid cognitive decline. The patients are participants at one of the nine Alzheimer's Disease Research Centers of California. Rapid decline was defined as a 3-point or greater loss on the Mini-Mental State Examination (MMSE) per year, post visit. The independent variables were age at clinic visit, age at symptom onset of AD, MMSE at patient visit, years of education, gender, ethnicity, living arrangement, presence of aphasia, delusions, hallucinations, and extrapyramidal signs. Receiver operating characteristic curve analysis indicated that AD patients presenting with moderate to severe aphasia, age at clinic visit of 75 years or less, and an MMSE greater than 7 were at increased risk for rapid cognitive decline. This information could help clinicians target these patients for pharmacologic interventions, facilitate long-term care planning, and potentially create savings by delaying or stabilizing the course of the disease.

Abstract

The reason for differences in rate of cognitive decline in AD is unknown. The interleukin-1 alpha (IL-1 alpha) -889 *2 allele is associated with increased risk for AD. Surprisingly, in a sample of 114 patients followed for an average of 3.8 years, individuals homozygous for the IL-1 alpha -889 *1 allele declined significantly more rapidly on the Mini-Mental State Examination than did others. There was no difference in rate of decline between patients with and without the APOE epsilon 4 allele. These results support the hypothesis that inflammation is important in the clinical course of AD.

Abstract

This study examined the relationships between regional cortical and hippocampal brain volumes and components of remote memory (recall, recognition, sequencing, and photo naming of presidential candidates) in 13 individuals with Alzheimer's disease (AD). Recognition and sequencing of remote memory for public figures were associated with regional cortical volumes. Specifically, lower recognition and sequencing scores were associated with smaller parietal-occipital cortical volumes; poorer sequencing was also associated with smaller prefrontal cortical volumes. By contrast, poorer anterograde but not remote memory scores were correlated with smaller hippocampal volumes. Within the constraints of the brain regions measured, these findings highlight the importance of the posterior cortical areas for selective remote memory processes and provide support for the dissociation between cortically mediated remote memory and hippocampally mediated anterograde memory.

Abstract

The authors recorded event-related brain potentials (ERPs) to picture primes and word targets (picture-name verification task) in patients with Alzheimer's disease (AD) and in elderly and young participants. N400 was more negative to words that did not match pictures than to words that did match pictures in all groups: In the young, this effect was significant at all scalp sites; in the elderly, it was only at central-parietal sites; and in AD patients, it was limited to right central-parietal sites. Among AD patients pretested with a confrontation-naming task to identify pictures they could not name, neither the N400 priming effect nor its scalp distribution was affected by ability to name pictures correctly. This ERP evidence of spared knowledge of these items was complemented by 80% performance accuracy. Thus, although the name of an item may be inaccessible in confrontation naming, N400 shows that knowledge is intact enough to prime cortical responses.

Abstract

In a 24-patient case series from retrospective chart review, the authors examined the use of gabapentin for the treatment of aggressive and agitated behaviors in nursing home patients with a DSM-IV diagnosis of dementia. On Clinical Global Rating Scale scores, 17 of 22 patients were much or greatly improved; 4 were minimally improved; and only 1 remained unchanged. Two of the 24 patients discontinued use of the medication because of excessive sedation. No other significant side effects were noted in treatment lasting up to 2 years.

Abstract

Comparative study of CSF levels of tau and AD7C-neuronal thread protein (NTP) in patients with AD and control subjects.AD is characterized by neurofibrillary tangles composed of the abnormally hyperphosphorylated microtubule-associated protein tau. AD7C-NTP is a proposed AD marker expressed at early stages of neurofibrillary degeneration.Enzyme-linked immunosorbent assays specific for tau and AD7C-NTP. CSF samples were obtained from 35 demented patients (25 with antemortem clinical diagnosis of probable AD, 5 with neuropathologic diagnosis of definite AD, 5 with Lewy body pathology), 29 nondemented patients with PD, and 16 elderly healthy control subjects. Receiver operating characteristics (ROC) and multivariate discriminant analysis for AD versus controls. Correlational analysis of CSF tau and AD7C-NTP and of each marker with Mini-Mental State Examination (MMSE) scores was performed.Levels of both tau and AD7C-NTP were significantly elevated in the AD patients compared with control subjects. ROC analysis showed that CSF tau distinguished between patients with AD and nondemented control subjects with 63% sensitivity and 89% specificity, AD7C-NTP with 70% sensitivity and 87% specificity. Combined evaluation of both markers with discriminant analysis raised the specificity to 93% at a 63% sensitivity level. Both markers positively correlated with each other within the AD group, but not among control subjects. CSF levels of AD7C-NTP, but not of tau, showed a small but significant inverse correlation (r = -0.43) with MMSE scores of AD patients.CSF levels of tau and AD7C-NTP may be useful biomarkers for AD.

Abstract

Content and contextual memory for remote public figures and events was assessed with a modified version of the Presidents Test in patients with Alzheimer's disease (AD) or Parkinson's disease (PD). Contributions of executive functioning, semantic memory, and explicit anterograde memory to remote memory abilities were also examined. The AD group had temporally extensive deficits in content and contextual remote memory not accountable for by dementia severity. The PD group did not differ from the control group in remote memory, despite anterograde memory impairment. These results support the position that different component processes characterize remote memory, various mnemonic and nonmnemonic cognitive processes contribute to remote memory performance, and anterograde and remote memory processes are dissociable and differentially disrupted by neurodegenerative disease.

Abstract

Several clinical criteria have been developed to standardize the diagnosis of vascular dementia (VaD). Significant differences in patient classification have been reported, depending on the criteria used. Few studies have examined interrater reliability.To assess the concordance in classification and interrater reliability for the following 4 clinical definitions of VaD: the Hachinski Ischemic Score (HIS), the Alzheimer Disease Diagnostic and Treatment Centers (ADDTC), National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN), and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).Structured diagnostic checklists were developed for 4 criteria for VaD, 2 criteria for Alzheimer disease (AD), and 4 criteria for dementia. Twenty-five case vignettes, representing a spectrum of cognitive impairment and subtypes of dementia, were prepared in a standardized clinical format. Concordance in case classification using different criteria and interrater reliability among 7 ADDTCs given a specific set of criteria was assessed using the kappa statistic.The frequency of a diagnosis of VaD was highest using the modified HIS or DSM-IV criteria, intermediate using the original HIS and ADDTC criteria, and lowest using the NINDS-AIREN criteria. Scores for interrater reliability ranged from kappa = 0.30 (ADDTC) to kappa = 0.61 (original HIS).Clinical criteria for VaD are not interchangeable. Depending on the criteria selected, the reported prevalence of VaD will vary significantly. The traditional HIS has higher interrater reliability than the newer criteria for VaD. Prospective longitudinal studies with clinical-pathological correlation are needed to compare validity.

Abstract

alpha2 Macroglobulin is a panproteinase inhibitor that is found immunohistochemically in neuritic plaques, a requisite neuropathologic feature of AD. Recently, a pentanucleotide deletion near the 5' end of the "bait region" of the alpha2 macroglobulin (A2M) gene was reported to be associated with AD in a large cohort of sibpairs, in which the mutation conferred a similar odds ratio with AD as the APOE-epsilon4 allele for carriers of at least one copy of the A2M gene (Mantel-Haenszel odds ratio, 3.56).We studied three independent association samples of AD patients (n = 309) with an age range of 50 to 94 years and representative controls (n = 281) to characterize the allele frequency of the pentanucleotide deletion in this cohort. We detected the mutation near the 5' splice site of exon 18 using standard PCR and restriction fragment length polymorphism methods. The results were adjusted for age, gender, education, and APOE polymorphism.We found that the A2M gene polymorphism conferred an increased risk for AD, with an estimated Mantel-Haenszel ratio of 1.5 (95% CI 1.1 to 2.2; p = 0.025). There was no age- or gender-dependent increase in A2M gene allele frequencies in AD patients compared with controls. The combined sample showed the expected association between AD and APOE-epsilon 4. In one of our three samples there was an interaction between the A2M and APOE-epsilon4 genes, but the other two samples showed no interaction between the two risk factors.Our data support an association between the A2M gene and AD. This association is less pronounced, however, in our cohort than in the previously reported sample of sibpairs.

Abstract

This study examined the relationships between regional brain volumes and semantic, phonological, and nonverbal fluency in 32 participants with Alzheimer's disease (AD). Object but not animal semantic fluency correlated with frontal and temporal gray matter volumes. Phonological fluency was not significantly associated with any brain volume examined. Nonverbal fluency was selectively associated with bilateral frontal gray matter volumes. Hippocampal volumes, although markedly reduced in these patients, were not related to any of the fluency measures. Results lend evidence to the importance of the frontal lobes in the directed generation of nonverbal and verbal exemplars by AD patients. Furthermore, both left- and right-hemisphere regions contribute to the generation of verbal and nonverbal exemplars.

Abstract

The Clock Drawing Test (CDT) is widely used in the assessment of dementia and is known to be sensitive to the detection of deficits in neurodegenerative disorders such as Alzheimer's disease (AD). CDT performance is dependent not only on visuospatial and constructional abilities, but also on conceptual and executive functioning; therefore, it is likely to be mediated by multiple brain regions. The purpose of the present study was to identify component cognitive processes and regional cortical volumes that contribute to CDT performance in AD. In 29 patients with probable AD, CDT performance was significantly related to right-, but not left-hemisphere, regional gray matter volume. Specifically, CDT score correlated significantly with the right anterior and posterior superior temporal lobe volumes. CDT scores showed significant relationships with tests of semantic knowledge, executive function, and visuoconstruction, and receptive language. These results suggest that in AD patients, CDT performance is attributable to impairment in multiple cognitive domains but is related specifically to regional volume loss of right temporal cortex.

Abstract

The pattern of deterioration in patients with Alzheimer's disease is highly variable within a given population. With recent speculation that the apolipoprotein E allele may influence rate of decline and claims that certain drugs may slow the course of the disease, there is a compelling need for sound statistical methodology to address these questions. Current statistical methods for describing decline do not adequately take into account between-patient variability and possible floor and/or ceiling effects in the scale measuring decline, and they fail to allow for uncertainty in disease onset. In this paper, the authors analyze longitudinal Mini-Mental State Examination scores from two groups of Alzheimer's disease subjects from Palo Alto, California, and Minneapolis, Minnesota, in 1981-1993 and 1986-1988, respectively. A Bayesian hierarchical model is introduced as an elegant means of simultaneously overcoming all of the difficulties referred to above.

Abstract

'Stages', as used in clinical practice and research, are defined, their value described, and criteria are proposed for their evaluation. The specific interest is in staging Alzheimer's disease (AD). Two staging systems, one based on the Global Deterioration Scale (GDS) and one based on the Mini-Mental State Exam (MMSE), are compared in terms of these criteria, as an illustration of the process involved. We propose that there is not one unique staging system, that different staging criteria might be appropriate to different research or clinical needs, depending on which part of the temporal course of the disease is of primary interest, and on whether the focus is on cognitive, functional, neurological, behavioral, economic, or other issues. GDS staging seems a better choice for the later stages of AD when the focus is on functional change. MMSE staging seems a better choice for tracking the earlier stages of AD when the focus is on cognitive change.

Abstract

Neuroimaging and lesion studies have demonstrated that hippocampal volume correlates with memory performance, but material-specific lateralization of this structure-function relationship has been inconsistent. This MRI study examined the relative contributions of left and right temporal lobe volumes to verbal and nonverbal recognition memory in a group of 20 Alzheimer's disease (AD) patients. There was a significant relationship between extent of right hippocampal and right temporal gray matter tissue volume deficit and performance on the face recognition subtest of the Warrington Recognition Memory Test. The face recognition test correlated with right hemisphere volume but not to left, indicating a material-specific relationship between brain structure and function in this patient group. Right temporal horn volume did not account for a significant proportion of variance in face recognition memory. Although word recognition was not significantly correlated with either left or right hippocampal volume in the total group, there was a strong correlation between left hippocampal volume and word recognition memory in the female AD patients. Thus, face recognition shows a material specific relationship with select lateralized hippocampal and temporal cortical volumes in AD patients, regardless of gender, whereas the verbal recognition-left-hippocampal volume relationship may be mediated by gender.

Abstract

We investigated the relationship between basal cortisol and dehydroepiandrosterone (DHEA) levels and impairment in different cognitive and noncognitive measures and the possible interaction of DHEA with hypercortisolemia in dementia in 27 patients diagnosed with Alzheimer's disease (AD). There were 17 men and 10 women. Patients were mildly to moderately cognitively impaired at the time of the initial cortisol measures. Patients were administered the Alzheimer's Disease Assessment Scale (ADAS) and Folstein Mini-Mental State Examination (MMSE) at approximately 6-month intervals. Cortisol and DHEA were determined using conventional 125I radioimmunoassay procedures. Pearson product-moment correlations among cortisol and DHEA measures and both initial and longitudinal clinical measures were calculated. There was a relationship between baseline 8 a.m. cortisol levels and cognitive function at the initial testing as measured by the ADAS cognitive measure, with higher cortisol levels being associated with a greater level of impairment. We did not document a relationship between cortisol or DHEA levels and noncognitive measures. There was a significant correlation between both the initial MMSE and ADAS cognitive measures and initial DHEA level, with lower DHEA levels unexpectedly being associated with better performance on these measures. The initial DHEA levels did not predict decline in cognitive function over time. These findings bring into question the potential usefulness of DHEA as a therapeutic agent.

Abstract

To examine whether each of the 5 Mattis Dementia Rating Scale (DRS) scores related to magnetic resonance imaging-derived volumes of specific cortical or limbic brain regions in patients with Alzheimer disease (AD).Relations between DRS measures and regional brain volume measures were tested with bivariate and multivariate regression analyses.The Aging Clinical Research Center of the Stanford (Calif) University Department of Psychiatry and Behavioral Science and the Geriatric Psychiatry Rehabilitation Unit of the Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif.Fifty patients with possible or probable AD. Magnetic resonance imaging data from 136 healthy control participants, age 20 to 84 years, were used to correct brain volumes for normal variation arising from intracranial volume and age.The DRS scores and volumes of regional cortical gray matter and of the hippocampus.Memory scores of the patients with AD were selectively related to hippocampal volumes. Attention and construction scores were related to several anterior brain volume measures, with attention showing a significantly greater association to right than left hemisphere measures. Initiation/perseveration scores were not significantly correlated with any measure of regional gray matter volume, but performance was related to prefrontal sulcal widening, with a greater association with the left than right sulcal volume.Certain DRS subtests are predictably correlated with selective regional brain volumes in AD. The specific relation between memory and hippocampal volumes and the nonsignificant relations between memory and regional cortical volumes suggest a dissociation between cortical and hippocampal contributions to explicit memory performance.

Abstract

To estimate the dollar savings in costs attainable from drug or other treatments for Alzheimer disease (AD) that stabilize or reverse patients' cognitive decline.Medical and other disease-related utilization data were collected from the caregivers of 64 patients diagnosed as having probable AD. The quantities of utilization were priced at national levels to generate measures of illness costs. Costs per patient were then estimated as regression functions of scores on the Mini-Mental State Examination (MMSE), which was used as an index of patient cognitive function. Potential savings in illness costs were estimated by comparing predicted costs at various baseline and intervention-level values of the patient's MMSE score.The potential savings in illness costs attainable from treatment are small for mildly and very severely demented patients with AD. However, for moderately to severely demented home-dwelling patients having, say, an MMSE score of 7 at baseline, prevention of a 2-point decline in the score would save about $3700 annually, and a 2-point increase in an MMSE score rather than a 2-point decline would save about $7100.Large savings in the costs of caring for moderately to severely demented home-dwelling patients with AD may be achievable from disease interventions that have minor effects on patients' cognitive status.

Abstract

The relationship between number of apolipoprotein E epsilon 4 (APOE epsilon 4) alleles and the rate of cognitive decline in patients with Alzheimer's disease was examined.Rate of decline in score on the Mini-Mental State was measured during the active phase of the decline curve between Mini-Mental State scores of 23 and 0. To characterize onset, the authors also estimated for each subject the age at which the Mini-Mental State score fell below 23 and obtained a retrospective report of age at onset from the caregiver. The number of APOE epsilon 4 alleles carried by each subject was determined from genomic DNA samples. The study included 86 subjects with probable Alzheimer's disease who had had at least two cognitive evaluations (a mean of 5.6 evaluations per subject over an average period of 3.6 years).The results did not support an association between APOE epsilon 4 dosage and rate of cognitive decline. Age at onset and age at which the Mini-Mental State score fell below 23 were also not related to APOE epsilon 4 dosage. The APOE allele frequencies were similar to those in other studies of subjects with Alzheimer's disease, showing an enrichment of the epsilon 4 allele.Although the APOE epsilon 4 allele is a risk factor for Alzheimer's disease, there is no support of a strong association between APOE epsilon 4 dosage and rate of cognitive decline. The epsilon 4 allele did not predict age at onset. Methodological inconsistencies may account for discrepancies between these results and previous findings.

Abstract

The alpha 1-antichymotrypsin (ACT) A allele was recently associated with Alzheimer's disease (AD), and the ACT AA genotype was reported to be more frequent in AD subjects with the apolipoprotein E (APOE) epsilon4 allele. We examined ACT and APOE genotypes in a sample of 160 subjects with probable AD and in 102 elderly control subjects. ACT A allele frequencies were similar in AD subjects (0.503) and elderly controls (0.519). In addition, we found no evidence that in AD the AA genotype is more frequent in subjects with the APOE epsilon4 allele than in those without it. Our results do not support an association between the ACT A allele and AD.

Abstract

Automatic and effortful processes were investigated using event-related brain potentials (ERPs) recorded from moderately impaired subjects with probable Alzheimer's Disease (AD), normal elderly, and normal young controls. The effects of effortful attention on ERPs to loud noises and the effects of stimulus intrusiveness on effortfully elicited ERPs were studied. First, ERPs to task relevant and irrelevant startling noises were compared. Second, ERPs to startling noises and moderate tones were compared when both were targets. The effects of age (young vs. elderly controls) and effects of dementing disease (AD subjects vs. elderly controls) were also assessed. Effortful attention augmented noise-elicited P300 amplitude in elderly subjects, but not in young. Intrusiveness augmented task-relevant P300 amplitude in young subjects, but not in elderly. Neither variable affected P300 amplitude in AD subjects. Thus, effects of age and disease depended on how P300 was elicited: when effortfully elicited, P300 amplitude was affected by disease but not age; when automatically elicited, P300 amplitude was affected by age but not disease. N1 effects differed from P300 effects.

Abstract

Concerns have been expressed that patients with dementia will display disinhibited, inappropriate sexual behavior. Retrospective research suggests that this is rare, but no observational research has been reported. The purpose of this study was to conduct such an observational study.Subjects were 40 patients with a dementia diagnosis who were living in institutional settings; subjects ranged in age from 60 to 98. Coders observed subjects on nine separate occasions, three in the morning, three in the afternoon, and three in the evening. Subjects were observed in multiple situations; coding included appropriate, ambiguous, and inappropriate sexual behaviors. Reliability coding was obtained for 42% of the patients on 11% of coded episodes.Behaviors could be coded with high reliability (94% to 100% across categories of behavior). On average, patients displayed 43 appropriate sexual behaviors, 1.48 ambiguous behaviors, and .83 inappropriate behaviors across the nine observation periods. This was not evenly distributed across patients, however; only 18% of patients ever displayed a sexually inappropriate behavior, and these were usually brief and minor. Inappropriate sexual behavior was observed in only 1.6% of the observed one-minute time segments.Observational research documents what had been previously suggested by retrospective reports: inappropriate sexual behavior is uncommon in dementia patients and brief and minor even when it occurs. Ambiguous behaviors, such as appearing in public incompletely dressed, which could suggest exhibitionism but more likely reflects self-care deficits, were more common. Misinterpretation of these events may be the source for some of the persistent lore regarding sexually disinhibited behavior in dementia patients.

Abstract

Patients with Alzheimer's disease (AD) show considerable heterogeneity in the rate at which they decline cognitively. The biological basis for this heterogeneity is unknown. We genotyped 86 subjects with diagnoses of probable AD to determine if they carried the alpha-1-antichymotrypsin (ACT) A allele, which has been associated with AD, or the CYP2D6 B mutant, found at increased frequency in the Lewy body variant (LBV) of AD. We then examined longitudinally-collected cognitive data to determine if these genetic markers were associated with rate of cognitive decline. Our results indicate that neither the ACT A allele nor the CYP2D6 B allele have a significant association with rate of decline on the Folstein Mini Mental State examination. Further, subjects with both the ACT A allele and the apolipoprotein epsilon 4 allele showed no evidence of accelerated decline. These findings suggest that any increased risk of developing AD or LBV conferred by these markers is not necessarily accompanied by a more rapid rate of decline.

Abstract

The status of semantic priming in Alzheimer's disease (AD) was examined using the speech elicited N400 component of the event-related brain potential (ERP). Speech was naturally paced, with 1 s of silence before the final word. In the semantic task, subjects attended to the meaning of the sentences for a subsequent memory test. In the phonemic monitoring task, they counted the words beginning with the letter 'p'. The effects of age were assessed by comparing young and elderly, and the effects of disease by comparing elderly and AD subjects. In healthy young and elderly subjects, N400s were large to semantically unprimed words and small to semantically primed words. In AD subjects, N400s were large to primed words, reflecting a failure of the sentence stem to prime the final word, and probably an impairment in semantic knowledge. The N400 priming effect was not smaller during the phonemic than semantic task in any group, suggesting that the semantic qualities of speech are processed even when subjects are attending to phonemic qualities. N400 latency was delayed with age and further delayed with dementia.

Abstract

Youth violence poses a major public health problem. It is important to find treatable predictors of recidivism. Our Subjects had committed offenses of physical and sexual assault. The personality dimensions of restraint and distress were rated by two independent and blind raters from narratives of offender's committing offenses, which were obtained at baseline during incarceration. Inter and intrarater kappas for each narrative were significant. In a 10-13 year follow-up, subjects lowest in self- restraint had significantly higher recidivism and their reoffenses differed in quality. Restraint may be influenced by clinical intervention and constitutes a new target in the treatment of delinquents.

Abstract

This study used a semiautomated image analysis technique to quantify the rate and regional pattern of cerebrospinal fluid (CSF) volume changes in the computed tomographic brain examinations of healthy adults and patients with Alzheimer's disease (AD).Longitudinal, within-subject design, with statistical correction for longitudinal method error (eg, head repositioning effects).Palo Alto (Calif) Department of Veterans Affairs Medical Center.The 41 patients with AD were recruited from the Geriatric Psychiatry Research Unit and the National Institute of Mental Health Clinical Research Center of the Palo Alto Department of Veterans Affairs Medical Center. The 35 healthy control subjects were recruited from the local community.Cerebrospinal fluid volumes estimated from computed tomographic scans.Even after accounting for an estimate of method error (eg, head positioning effects) across computed tomographic examinations, the patients with AD showed greater annual CSF volume increases than did the control group. This CSF volume enlargement was not uniform across brain regions of interest; rather, the patients with AD showed disproportionate volume increases in the ventricular system and the sylvian fissures. Greater CSF volume changes in the patients with AD were significantly associated with greater cognitive decline on the Mini-Mental State Examination. Furthermore, younger patients with AD showed more rapid progression on computed tomographic scans than did older patients.The rate of CSF volume enlargement is region specific, with the most marked annual rate of change occurring in the ventricular system and the sylvian fissures. In addition, younger patients show more rapid progression in the ventricular and frontal sulcal brain regions of interest than do older patients.

Abstract

To study the relationship between estrogen hormone replacement therapy and recall of proper names and words in cognitively intact older women.A case-control study using subjects matched on age and education.From a group of 278 older (age range 55 to 93 years) community-dwelling women volunteers for memory research, 72 older women taking estrogen replacement therapy were matched on age and education with a group of 72 women not taking estrogen.Dependent measures were performances on: a proper name recall test and a word recall test.Proper name recall was significantly better in those receiving estrogen (mean = 4.3; SD = 3.3) than in those not receiving estrogen (mean = 3.1; SD = 2.5), P = 0.01. There was also significantly greater variance in the name recall scores of the group taking estrogen than in the group not taking estrogen. For word recall, there was no significant difference between those subjects taking estrogen (mean = 6.4; SD 3.8) and those not taking estrogen (mean = 5.8; SD 3.7), P > 0.10.Estrogen use was associated with enhanced recall of proper names. Previous failures to find differences associated with estrogen use may reflect the memory measures used or an increased inter-individual variability of the estrogen-taking group, as was observed in the present study. Interpretation of these results should be tempered by their retrospective nature.

Abstract

To expand on a recent study of 42 patients with probable Alzheimer's Disease that found that the only significant predictors of certain clinical end points were the degree of severity features at entry ("how far").A case series study of a cohort of 81 patients with Alzheimer's disease that used survival analysis methods similar those of the previous study but included a new technique for calculating rate of progression ("how fast") as well as entry characteristics ("how far").A university medical center and its affiliated Veterans Affairs Medical Center.All patients with probable and definite Alzheimer's disease studied at the Aging Clinical Research Center at Stanford University, Palo Alto, Calif, in the years 1981 and 1992 who met the following criteria: a mild to moderate level of severity of the disease (Mini-Mental State Examination score of 15 or above) at entry into the study and a minimum of three test points spaced approximately 6 months apart (to allow estimation of rate of progression). A total of 81 such patients were identified. These patients had been followed up for a mean of 4.53 +/- 2.3 years, with a range of 1.0 to 14.5 years.The outcome measure was the average rate of decline on the Mini-Mental State Examination.The results of our study replicated a previous finding that the degree of severity is a strong predictor of time course, but in addition we found that the rate of progression also appears to be a strong predictor of clinical course.There appears to be substantial heterogeneity in the rate of progression in patients with Alzheimer's disease, and, like initial degree of severity, rate of progression appears to be a strong predictor of clinical course.

Abstract

We examined the relation between selected psychiatric symptoms and the average rate of decline in different areas of cognition in patients with Alzheimer's disease. Measures of decline were computed by determining patients' average rates of decline on the underlying factors of the Mini-Mental State Examination (MMSE). Patients with agitation or wandering declined more rapidly on the total MMSE score than did patients without either symptom. The Following Commands factor accounted for almost all of this decline. The findings suggest a relation between the presence of certain behavioral problems in Alzheimer's disease and decline in particular cognitive areas.

Abstract

The purpose of this paper was to use the Wechsler Adult Intelligence Scale (WAIS) to further define the nature of the underlying factors of the Mini-Mental State Examination (MMSE) as proposed by Tinklenberg et al. (1990). The MMSE was administered to 51 patients once every 6 months for at least one year; the WAIS was administered only at the beginning of the study. Stepwise regression analyses yielded these results: for the Following Commands factor, the best correlate was the Comprehension subtest; for the Language Repetition factor, the best correlate was the Picture Arrangement subtest; and for the Language Expression factor, the best correlates were the Digit Symbol and Object Assembly subtests. These relations help clarify the correlates of decline of AD patients on the MMSE.

Abstract

The reverse transcription and polymerase chain reaction technique (RT-PCR) was assessed for the quantification of changes in mRNA levels from primary astrocyte cultures. The effects of dibutyryl cyclic AMP (dBcAMP) on glial fibrillary acidic protein (GFAP) mRNA and the effects of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and lipopolysaccharide (LPS) on interleukin-6 (IL-6) mRNA were examined. Two quantitative PCR methods were used: one involved carrying out the reaction in the exponential phase and the other involved the coamplification of a competitive target sequence. Increased GFAP mRNA in response to chronic dBcAMP treatment and increased IL-6 mRNA in response to TNF-alpha/IL-1 beta were readily detected. Both RT-PCR techniques were found to be suitable for the detection of large as well as smaller (twofold) changes in mRNA levels. The advantages and limitations of RT-PCR for mRNA quantification are discussed.

Abstract

This study examined the time-course of alcohol impairment of general aviation pilot simulator performance. We tested 14 young (mean age 25.8 years) and 14 older (mean age 37.9 years) pilots in a Frasca 141 simulator during alcohol and placebo conditions. In the alcohol condition, pilots drank alcohol and were tested after reaching 0.10% BAL, and then 2, 4, 8, 24, and 48 h after they had stopped drinking. They were tested at the same times in the placebo condition. Alcohol impaired overall performance. Alcohol impairment also depended on the order in which subjects participated in the alcohol and placebo sessions, with larger decrements for the alcohol-placebo order than for the opposite order. To examine the influence of alcohol independent of session order effects, we compared performance in the first alcohol session with performance in the first placebo session. This analysis showed that alcohol significantly reduced mean performance in the alcohol condition at 0.10% BAL and at 2 h. In addition, alcohol increased variability in performance in the alcohol session from 0.10% BAL to 8 h, suggesting that some subjects were more susceptible to alcohol than others. Older pilots tended to perform some radio communication tasks less accurately than younger pilots.

Abstract

The purpose of this study was to compare the stage and the subtype models of disease progression in Alzheimer's disease. The authors address the issue of whether the overall rate of clinical decline is different in Alzheimer's disease patients with and without early development of aphasia, apraxia, or agnosia.The study was a case series study. Two separate cohorts of Alzheimer's disease patients were used, one from an ongoing single center study at Stanford University (N = 57) and the other from a multicenter project across the state of California (N = 70). Patients were assessed every 6 months in the Stanford study and yearly in the state study. All patients were assessed at least three times. The outcome measure was the average rate of decline on the Mini-Mental State examination.The average rates of decline on the Mini-Mental State were computed for each subject. Subjects were then divided among groups according to whether and when they exhibited aphasia, agnosia, or apraxia. The effects of the presence of aphasia, agnosia, or apraxia were assessed by comparing the average rates of decline on the Mini-Mental State.Alzheimer's disease patients who developed aphasia or apraxia declined more rapidly than those patients who did not develop either sign. These results were not attributable to differences in Mini-Mental State scores at entry into the study. The results suggest the presence of subtypes of Alzheimer's disease in which accelerated decline is associated with the early appearance of certain neurological signs.

Abstract

This study used a semiautomated analysis technique to quantify differences in regional brain cerebrospinal fluid volumes observed with computed tomography between healthy adults and patients with Alzheimer's disease (AD).Cross-sectional, between-subject design, using an age-regression model.Palo Alto (Calif) Department of Veterans Affairs Medical Center.The 117 patients with probable or definite AD were recruited from the Geriatric Psychiatry Research Unit and National Institute of Mental Health Clinical Research Center of the Palo Alto Department of Veterans Affairs Medical Center. The 114 healthy volunteers were recruited from the local community.Cerebrospinal fluid volumes estimated from computed tomographic scans and neuropsychological test scores.The computed tomographic estimates of ventricular and sulcal cerebrospinal fluid volumes increased significantly in all sampled brain regions in normal aging and were vastly larger in AD than in normal aging. Furthermore, younger patients with AD had significantly greater cerebrospinal fluid volume enlargement than did older patients with AD compared with healthy controls of their age. When the AD group was divided on the basis of reported age at symptom onset, patients in the early-onset group (onset before age 65 years) were quantitatively more abnormal than and showed a different pattern of abnormality from the patients in the late-onset group. This onset difference was also evident in neuropsychological test performance.This cross-sectional study revealed a number of converging findings that suggested greater abnormality in the early-onset than in the late-onset group of patients with AD. The possibility remains, however, that the two onset groups represent different stages along a continuum of pathologic changes.

Abstract

We examined how pilot age influences radio communication and routine flying tasks during simulated flight, and if practice reduces age differences in these tasks. The communication task involved reading back and executing messages with four commands (heading, altitude, communication frequency, transponder code). Routine flying tasks included takeoff, visual approach, and landing. Fifteen older (X = 38.4 years) and 16 younger (X = 26.1 years) private-license pilots flew 12 flights involving these tasks. Age differences were found in the communication task; older pilots read back and executed controller messages less accurately. However, age differences were not significant for any of the routine flying tasks except the approach. Age differences in communication performance were not reduced by practice, with older and young pilots improving at roughly the same rate across flights. These results are consistent with previous research showing age-related declines in working memory capacity. Capacity declines would produce greater age differences on communication than on routine flying tasks because the communication tasks imposed a greater load on working memory.

Abstract

1. Alzheimer's disease (AD) is likely to have a significant effect on sexual behavior, but both patient and partner will still have sexual feelings and needs. 2. Research has shown that a high proportion of men with AD develop erection problems, but causes of their erection difficulties are not understood. 3. Research has shown that inappropriate sexual behavior in AD patients is uncommon, although it can be very troubling to the family and health-care provider if it occurs. 4. More professionals need to be trained to discuss sexual issues openly and sensitively with AD patients and partners and to offer useful clinical suggestions.

Abstract

The nucleus basalis of Meynert (nbM) was examined using immunocytochemistry for beta-amyloid precursor protein (beta APP) expression in Alzheimer's disease (AD). In mild AD cases, light labeling of the cell body and proximal processes was observed, and small intracellular structures were labeled rarely. In the more severe cases, intense cytoplasmic beta APP labeling was seen, often along with small beta APP-positive structures. Double-labeling experiments demonstrated that in the more severe cases these small structures were also decorated by a neurofibrillary tangle (NFT) antiserum. Other neurons in the severe cases showed incorporation of beta APP into large inclusions, which were also labeled with the NFT antiserum. However, some large inclusions in the severe cases were labeled by the NFT antiserum but contained no beta APP. Extraneuronal NFTs did not show beta APP labeling and did not react with an antibody to the beta-amyloid peptide. These results suggest that increased expression of beta APP coincides with intracellular NFT formation in the nbM, but that the formation of extraneuronal NFTs results in a loss of beta APP immunoreactivity.

Abstract

Change in memory performance and its correspondence to change in speed of performance and self-reported memory functioning were investigated longitudinally in 30 older adults with memory complaints. Subjects were assessed by self-report questionnaires and cognitive tests 3 times, at near 2-year intervals. A significant decline in word-recall scores was found, which was accompanied at the group level by significant self-reported decline in everyday memory functioning and nonsignificant decline in Wechsler Adult Intelligence Scale Digit Symbol scores (alpha = .05). The oldest subjects showed the most substantial declines in memory performance. At the individual level, however, memory change did not significantly correlate with either change in self-reports or change in Digit Symbol scores. Although these results do not support a cognitive slowing model of decline at the intraindividual level, they do have implications for intervention of age-related memory decline.

Abstract

beta-Amyloid precursor protein (beta APP) mRNA was examined in peripheral mononuclear blood cells (PMBCs) in Alzheimer's disease, Down's syndrome and control subjects. Total RNA from PMBCs was reverse transcribed and then amplified using the polymerase chain reaction (PCR). The 3 major beta APP transcripts were expressed in PMBCs from all subjects. These results suggest that PMBCs could be a circulating source for abnormal amyloid deposition in the brain and in peripheral tissues.

Abstract

The anatomic distributions of beta-amyloid peptide (beta AP) and beta-amyloid precursor protein (beta APP) in the medial temporal lobe were examined with immunocytochemistry in Alzheimer's disease. beta AP-containing plaques were found most frequently in the cortical and basal regions of the amygdala, and in the hippocampal CA1, subiculum, and dentate molecular layer. beta APP expression in plaques was found in a similar distribution, with some, but not all beta AP plaques also showing beta APP. In the cortical and basal amygdala, some cases showed beta APP in the centers of plaques, whereas in the hippocampus, all cases displayed beta APP mainly in plaque neurites. The lateral regions of the amygdala contained mainly diffuse beta AP plaques which had little beta APP. These findings suggest that although beta APP expression and beta AP deposition generally colocalize, processing of beta APP may vary among closely interconnected anatomic regions.

Abstract

We treated 149 patients meeting criteria for age-associated memory impairment (AAMI) for 12 weeks with a formulation of phosphatidylserine (100 mg BC-PS tid) or placebo. Patients treated with the drug improved relative to those treated with placebo on performance tests related to learning and memory tasks of daily life. Analysis of clinical subgroups suggested that persons within the sample who performed at a relatively low level prior to treatment were most likely to respond to BC-PS. Within this subgroup, there was improvement on both computerized and standard neuropsychological performance tests, and also on clinical global ratings of improvement. The results suggest that the compound may be a promising candidate for treating memory loss in later life.

Abstract

We investigated the relationship between extrapyramidal signs (EPSs) in patients diagnosed with Alzheimer disease (AD) and the average rate of decline in different areas of cognition. The presence of tremors, cogwheel rigidity, or bradykinesia were scored as EPS using the California State Department of Health Services AD Diagnostic and Treatment Center Form. Measures of decline were computed by determining patients' average rates of decline on the Mini-Mental State Examination (MMSE). Of the 81 patients, 24 were determined to have EPS not related to medications. Overall, patients with EPS deteriorated 67% faster on MMSE (4.5 points per year) than did patients with no evidence of EPS (2.7 points per year). Our findings indicate that the clinical presence of EPS is a poor overall prognostic sign in patients with a clinical diagnosis of AD.

Abstract

Most patients with Down's syndrome (DS) undergo a premature cognitive decline with aging, and eventually develop the neuropathologic changes of Alzheimer's disease (AD), including amyloid-containing neuritic plaques, and the formation of neurofibrillary tangles. The amygdala is a focus of marked neuropathologic change in older patients with DS and in AD. We examined the amygdala with immunocytochemical and histochemical methods in 6 cases with DS, ages 19, 20, 27, 29, 56 and 64 years and compared them to 4 cases with AD, ages 54, 76, 77 and 80 years. An antiserum to the A4 amyloid peptide demonstrated amyloid deposition in plaques in all 10 cases. Plaques were also revealed in all cases by the Alcian blue stain for glycosaminoglycans and by the Bielschowsky and Bodian silver stains. An antiserum to alpha-1-antichymotrypsin (ACT) showed plaques in the AD cases and in the 19, 56 and 64 year old DS cases. Neurofibrillary tangles were observed with silver stains only in the older DS and in the AD cases, and not in the 19, 20, 27 and 29 year old DS cases. Likewise, antisera to paired helical filament, to microtubule associated proteins tau and microtubule associated protein-2 (MAP-2), and to ubiquitin, all of which are components of neurofibrillary tangles, reacted with tangles and abnormal neurites only in the older DS and the AD cases. An antiserum to neurofilament epitopes labeled NFTs in the older DS cases and the AD cases, but not in the younger DS cases, except for two intraneuronal NFTs in the 27 year old case.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Patients with presumptive Alzheimer's disease (AD) and healthy community volunteers received computed tomographic (CT) brain scans and cognitive tests. The CT scans were quantitatively analyzed with a semiautomated thresholding technique to derive volumetric measures of cerebrospinal fluid (CSF)-to-tissue ratios in six regions of interest (ROIs): lateral ventricles; vertex sulci, frontal sulci, Sylvian fissures, parieto-occipital sulci, and third ventricle. Regression analysis was performed on CT data from 85 older volunteers (ages 51-82) to generate age norms for each ROI. Within this group, tissue loss, as measured by the % CSF in each ROI, was highly correlated with age, although each ROI showed different rates of change over age. For all ROIs, the AD group had significantly more tissue loss than expected in normal aging. In addition, AD patients with a presenescent onset (before age 65) tended to have greater vertex sulcal and frontal sulcal tissue reduction than AD patients with a senescent onset (age 65 or after). When regional tissue reduction, corrected for age, was correlated with cognitive test scores, two sets of double dissociations emerged within the AD group: large CT z scores (i.e., decreased tissue and increased CSF) of frontal sulci, but not of the third ventricle, correlated with low Comprehension and Boston Naming Test scores, whereas large CT z scores of the third ventricle, but not of the frontal sulci, correlated with low scores on Digit Symbol and Picture Arrangement. These results suggest that heterogeneity of structural and functional integrity exists among patients with AD.

Abstract

The Mini-Mental State Examination (MMSE) is a commonly used instrument for assessing mental impairment. Previous proposals for its underlying structure have focused on scores obtained from a single administration of the test. Because the MMSE is widely used in longitudinal studies, we examined the pattern of relations among the rates of chance of the items. Data were obtained from 63 subjects for 1.5 years or more. The relations among the rates of change of the MMSE items were described by a five-factor solution that accounted for 75% of the variance and comprised factors pertaining to orientation and concentration, obeying commands, learning and repetition, language, and recall. This was in contrast to the structure of the scores obtained from a single administration of the MMSE, which was best described by a two-factor solution. In order to provide a clinical validation, factor scores derived from the MMSE factors were used to predict scores on the Memory and Behavior Problems Checklist and the Brief Cognitive Rating Scale.

Abstract

Loss of erection was reported in 53% of 55 male Alzheimer's disease patients with a mean age of 70.25. Loss of erection is not related to degree of cognitive impairment, age, or depression. Modal time of onset of erectile problems is concurrent with onset of Alzheimer's symptoms. Patients with erectile problems were not taking more medications overall than those without problems and had no greater overall incidence of concurrent physical problems. Thus, the evidence suggests that there may be an elevated incidence of erectile failure in patients with Alzheimer's disease as a primary problem not attributable to other age-related factors.

Abstract

Dexmedetomidine, a highly selective and potent agonist at alpha-2 adrenoceptors, produces a hypnotic-anesthetic action in rats. The mechanism for this response may involve an inhibitory G-protein and increased conductance through a potassium channel. To investigate this, the effects of pertussis toxin, a specific inactivator of inhibitory G-proteins, and 4-aminopyridine, a blocker of potassium channels, on the hypnotic-anesthetic response to dexmedetomidine were studied in rats. Pertussis toxin and 4-aminopyridine both decreased the hypnotic-anesthetic action of dexmedetomidine in a dose-dependent fashion. To preclude the possibility that pertussis toxin and 4-aminopyridine attenuated the hypnotic-anesthetic action of dexmedetomidine via indirect central nervous system excitation, the effects of pertussis toxin and 4-aminopyridine on the hypnotic-anesthetic action of pentobarbital also were assessed. Pentobarbital-induced hypnosis was not attenuated by either treatment. These results suggest that the receptor-effector mechanism for the hypnotic-anesthetic action of dexmedetomidine involves an inhibitory G-protein and increased conductance through a potassium channel.

Abstract

1. Amyloid deposition is one of the pathologic hallmarks of Alzheimer's disease. Since the isolation of the beta-amyloid gene, which revealed that the amyloid forming 4 kD protein is part of a larger precursor, interest has focused on the process by which amyloid is generated and deposited. 2. The authors have developed an immunologic means of detecting amyloid precursor proteins in human brain. 3. The method involves the expression of human beta-amyloid precursor cDNA in a recombinant vaccinia virus, so that antibodies are produced against the precursor proteins in their native forms. 4. By using this expression system, the amyloid precursor immunogens incorporate post-translational modifications that normally occur in vivo; this cannot be achieved with small synthetic peptides. 5. Using antibodies to the 695 residue amyloid precursor, we have detected using Western blot analysis a protein of approximately 120 kD in samples of cerebral cortex from three subjects with Alzheimer's disease and one control subject. 6. Additional antibodies to other amyloid-related proteins have been developed. These are being used to assess the differential expression of the various amyloid precursors and subdomains in additional cases.

Abstract

Mental deterioration accompanying sleep apnea has been noted frequently. Because sleep apnea increases with age, such deficits raise the possibility that dementia in the elderly could be related to sleep apnea. In this study we investigated this possibility cross-sectionally by comparing respiration during sleep in 28 patients with Alzheimer's disease (AD) and 25 nondemented controls. We hypothesized that higher levels of sleep apnea would be present in AD patients. Our results indicated no significant differences between AD patients and controls but those few AD patients who desaturated during sleep experienced morning confusion. The findings imply that AD and sleep apnea are two separate conditions which may still interact in the aged.

Abstract

Latency to the first episode of rapid eye movement sleep (REML) has been proposed as a potential biomarker for Alzheimer's disease (AD). In this study, we compared REML values from 28 AD patients and 28 age- and sex-matched controls. We employed multiple definitions of REML and multiple cutoffs to classify patients and controls. Results indicated that the best REML definition and optimal cutoff criterion resulted in only 65% correct classifications. We discuss the longer REML in AD patients relative to controls in terms of both overall sleep disturbance and selective deterioration of the REM-cholinergic system. As REML may be relatively short in other forms of psychopathology (e.g., affective disorders), REML may still hold promise in the differential diagnosis of dementia and pseudodementia.

Abstract

Alzheimer's disease, an autosomal dominant disorder, is characterized by the presence of neurofibrillary tangles and senile extracellular plaques in the brain of affected individuals. An amyloid beta protein has been isolated from the core of these plaques, and the gene encoding this protein has been mapped to region q11.2 to q22.2 of chromosome 21. Independent linkage studies have shown that the locus responsible for familial Alzheimer's disease also maps to the long arm of chromosome 21. It is thus very tempting to speculate that a defect (or defects) of the amyloid beta protein gene is the cause of Alzheimer's disease. For this reason, we have done association studies between Alzheimer's disease and restriction fragment length polymorphisms of the amyloid beta protein gene locus. We report a study of six restriction fragment length polymorphisms at the human amyloid beta protein gene locus. Several haplotypes constitute very informative marker systems for this region of chromosome 21. One of the six polymorphisms, a 6.6/7.3 kb (kb = 10(3) base-pairs) EcoRI restriction fragment length polymorphism, is loosely associated with the presence of Alzheimer's disease in a population of 34 subjects.

Abstract

A study of 67 rapes by 63 California adolescents has yielded a highly representative composite picture of the typical rape episode by a juvenile assailant. Previously unexplored behavior patterns have emerged, including prior drug use, impulsivity, and lack of victim provocation. These findings have practical implications for clinicians treating rape victims and for the rehabilitation of adolescent rapists.

Abstract

In two studies, we studied the comparative sensitivity of different subjective and objective measures to methylphenidate (10 and 20 mg) and secobarbital (100 mg) versus placebo, and diphenhydramine (50 mg) and diazepam (10 and 20 mg) versus placebo in abstinent alcoholics. Subjective measures used were the Visual Analog Mood Scale and the Profile of Mood States. Objective measures were the Stroop and two microcomputer-controlled tasks developed in our lab - a dual pursuit tracking/reaction time task (P-Trak) and a reaction time task with regular and irregular preparatory intervals (PI) of varying length (Reactest). In addition, several baseline measures (Eysenck Personality Inventory, Spielberger State-Trait Anxiety Inventory and NIMH Mood Scale Elderly) were evaluated for their correlation to drug response. All three central nervous system depressants impaired performance on Reactest at the longer PIs and showed a main effect with irregular PIs, but only the 20-mg dose of diazepam impaired reaction time at the shortest PI and showed a main effect with regular PIs. On P-Trak, secobarbital and diazepam 20 mg impaired both tracking and reaction time, while methylphenidate 20 mg improved only the reaction time component. Only diazepam 20 mg affected mood. No effects were noted on the Stroop. The implications of these findings are discussed. Both P-Trak and Reactest with long PIs were more sensitive than VAMS, POMS or Stroop to drug effects. As lower doses of central nervous system depressants impaired reaction time only with longer PIs and showed a main effect only with irregular PIs, cognitive effects of these drugs may be missed if only subjective or short, regular PI tasks are examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

This randomized, double-blind study was designed to evaluate the effect of prostacyclin (epoprostenol) on the incidence and severity of postoperative neuropsychologic dysfunction in patients undergoing coronary artery operation. Four days before operation and 1 week after operation, 100 patients having coronary artery bypass grafting underwent detailed neurologic and psychologic examinations and computed tomographic scans of the brain. The psychologic examination was repeated 2 months after operation. During cardiopulmonary bypass, all patients received 300 U/kg of heparin and then either buffer-diluent or prostacyclin (12.5 ng/kg/min from the time of heparinization until onset of cardiopulmonary bypass and 25 ng/kg/min during cardiopulmonary bypass). No deaths or major neurologic complications occurred in this series. Ninety-six patients completed the psychologic and neurologic evaluations 1 week after operation; 74 of these patients were evaluated psychologically 2 months after operation. Psychologic testing demonstrated similar declines in postoperative performance in both the prostacyclin-treated and the control groups; these changes were no longer present in either group 2 months after operation. Results of neurologic examinations and computed tomographic scans of the brain were unchanged. We conclude that the administration of prostacyclin during cardiopulmonary bypass in patients undergoing routine coronary artery operation has no effect on perioperative cognitive changes.

Abstract

Fourteen Alzheimer subjects participated in a parallel group study of desamino-D-arginine-vasopressin (DDAVP, desmopressin). All subjects received one week of single-blind placebo. Then on a double-blind basis, the active group received DDAVP intranasally in doses starting at 30 micrograms per day and increasing over a 3 week period to 180 micrograms per day; the control group received an identical placebo. Using a repeated measures ANOVA, three measures out of thirty-one were found to be statistically significant for DDAVP treatment: the Hamilton depression scale and the affect and interpersonal subscales of the SCAG. However, the magnitude of these changes was probably too small to be clinically significant. Except for one subject who transiently became hyponatremic (Na of 120) and confused while receiving 180 micrograms of DDAVP, there were no adverse effects. There were no significant group changes in sodium, potassium, plasma osmolality, blood pressure, and weight.

Abstract

Memory is not a unitary process. Rather it is comprised of several psychobiologically distinct elements which may be selectively affected by drugs or by disease processes. An understanding of these distinctions allows a greater appreciation of normal and altered cognitive functioning. In this article, we review several different conceptual approaches to memory and underscore certain methodological issues that are particularly important in studying the psychopharmacology of memory.

Abstract

In this article we review the effects of specific drugs or neurotransmitter systems on cognitive functions. While much of what we know about drugs' effects on memory is derived from animal experiments, this review focuses on studies relevant to human clinical conditions. We conclude with a speculative analysis or taxonomy of the pharmacology of memory which broadly highlights the utility of viewing memory as being comprised of several differentiated processes.

Abstract

Ten normal male volunteers were administered oral diazepam (0.25 mg/kg) or placebo followed 45 min later by IV naloxone (1.2 mg) or placebo. Diazepam produced a marked decrement in performance on tests of memory, visual psychomotor skills, reaction time, and time production. Naloxone alone had no effect on these measures and failed to interact with the diazepam. These findings do not support a role of the endogenous opioid system in normal human cognitive processes or in the behavioral effects of diazepam.

Abstract

Vasopressin peptides have been shown to facilitate learning and memory in both animals and humans; however, the effectiveness in humans is controversial. In a double blind parallel group study, 17 demented subjects (either Alzheimer's or alcoholic) were given either desglycinamide-9-arginine-8-vasopressin (DGAVP) 92 micrograms intranasally TID or an identical placebo for 1 week after having received 1 week of placebo. To our knowledge, this is the first report of DGAVP being used in subjects with dementia. The DGAVP group had a statistically significant improvement on the Buschke list learning of low imagery words. However, for various reasons discussed in the paper, we feel this finding needs to be replicated before any definite conclusions can be drawn. Since there were no other appreciable behavioral effects of this DGAVP regimen, our results should be considered negative. There was no evidence of any DGAVP-related adverse effects, except for possible weight gain.

Abstract

The purpose of this paper is to present certain psychological tests adapted for computerized testing of subjects. The reasons why we have considered such tests are numerous: computerized test facilitate measurement of reaction time, testing conditions are standardized without reliance on performance of research assistants, data can be recorded on disc storage without paper handling, preliminary analyses and individual results can be available immediately after testing, simulation of certain real-life situations is possible, randomization of testing materials is facilitated. The computerized testing paradigms for use in gerontology to be discussed are: one an attention task of possible use in psychological research; the second a memory task aimed at basic cognitive psychological research and finally a performance task relating to a complex motor ability (flying). All provide inexpensive, reliable, quantified data and all use the same hardware. It is expected that this area will expand enormously and rapidly.

Abstract

In a single-blind study, 12 men (mean age 63 years) with senile dementia were given nafronyl in a dosage of 100 mg eight times daily for a week, followed by 100 mg four times daily for 12 weeks. Rigorous clinical, laboratory and psychometric assessments revealed no toxicity and no significant effects on vital functions. In the cerebrospinal fluid, the ratio of lactate to pyruvate decreased--a finding consistent with an increase in the aerobic metabolism of glucose.

Abstract

Ten healthy old and 10 healthy young subjects each received a series of trials in a memory retrieval task similar to that devised by Sternberg (1967). On each trial the subject saw a memory set of 2 or 4 digits (set size) followed by a probe. The task was to indicate whether the probe was a positive or negative instance (response type) of the memory set for that trial. On half the trials, the probe digits were degraded by a mask of random dots (stimulus quality). For both young and old subjects, RT was later to probes following the larger set size, later to degraded probes, and later to negative probes. For the young subjects only, P3 latency was delayed by the same variables affecting RT although to a lesser degree. P3 latency in the elderly responded quite differently: it was unaffected by set size or response type. However, P3 was somewhat delayed by the degraded probes suggesting that the failure to reflect set size or ceiling effect in the elderly. The correlation between single-trial P3 latency and RT in the elderly is lower than in the young. The data are discussed in terms of age-related differences in the meaning of P3 latency.

Abstract

Cranial computed tomography (CT) scans were obtained in 46 male chronic alcoholics and 31 normal male volunteers. Automated methods were used to estimate the cerebrospinal fluid (CSF) volume in various intracranial zones. Measures of the ventricular fluid volume, the volume of fluid in cortical areas on CT sections at the level of the ventricles, and the sulcal fluid volumes on two convexity sections were computed. The alcoholic group, excluding subjects with chronic liver disease, had significantly more fluid than the control group on all sulcal measures. The group difference on the ventricular measure fell short of significance. Within the alcoholic group, no significant correlation was found between the number of years of alcoholism and any fluid measure when normal age effects were taken into account. A striking degree of variability in the sulcal volumes was observed within the alcoholic group, with many subjects showing normal values while a large group showed markedly elevated values. Further studies will be necessary to determine the significance of these variations.

Abstract

This article is a review of the pharmacotherapy of senile dementia in Europe and the United States. Neurophysiological and neuropathological studies of demented elderly have suggested that a change from the attempt to improve cerebral blood flow to the attempt to improve neuronal intermediary (glycolytic) metabolism may be more fruitful therapeutically. Clinical studies of drugs which are direct smooth relaxant vasodilators are compared with studies of drugs claimed to improve neuronal intermediary metabolism in order to test this hypothesis. Comparison of 102 clinical studies of these two types of medications finds that a significant (p less than .005) number of studies of drugs with metabolic action claim positive results than to studies of drugs with vasodilatator action alone. Three new studies addressing questions of dose and spinal fluid effects of these medications are presented. Two studies provide evidence for the superiority of 6 mg/day of dihydroergotoxine mesylate to 3 mg/kg in the elderly. One study suggests that the medication naftidrofuryl, in doses of 800 mg/day and 400 mg/day, may have similar effects.

Abstract

Young normal subjects received 16 g of choline chloride in a double-blind A-B-A design. Short- and long-term memory function was evaluated. Comparison of group means indicated that choline chloride did not significantly affect short-term memory or long-term memory. However, individual subjects may have had some aspects of long-term memory affected by choline chloride treatments. The results suggest that the effect of lower doses of choline on long-term memory should be evaluated.

Abstract

Choline chloride (2 g QID) and placebo were administered to 10 subjects over age 60 in a placebo-drug placebo design. Subjects first took placebo for 7 days, followed by choline for 21 days and finally took placebo for another 21 days. Memory tests were given at the end of both placebo periods and twice during choline administration. Choline did not significantly affect performance on a test of memory storage, a test of retrieval from memory or on the digit span test. In addition, a correlational analysis showed that the difference between memory performance during choline administration and during placebo administration was not significantly related to baseline memory performance. These results, together with results of previous studies indicate that choline is not an effective agent for improving memory in nondemented elderly patients.

Abstract

Auditory brain stem and cortical evoked potentials were recorded from 15 schizophrenics and 15 controls. There were significant cortical evoked potential differences between the two groups. However, brain stem evoked potentials were almost identical, suggesting that the cortical evoked potential differences are not due to peripheral factors such as inability to match sensory thresholds or defects in auditory acuity.

Abstract

Sternberg's memory scanning task, Buschke's selective reminding task, and a time production task were given to 18 male subjects after they had received 10 mg of methamphetamine, 100 mg of secobarbital and placebo on separate days. Time production and learning that involved storage and retrieval of information in long-term memory were most sensitive to drug effects. Other measures of learning and memory scanning performance were not affected by either drug.

Abstract

Rhesus monkeys, pretreated with alpha-methyl-para-tryosine (AMPT) and subsequently injected with phenylethylamine (PEA), did not demonstrate the characteristic amphetamine-like PEA effects. However, when AMPT pretreatment was followed with l-dopa and then PEA injection, PEA effects were restored. These results are compatible with a dopamine theory of schizophrenia.

Abstract

The effects of ethanol and meperidine on the auditory evoked potential (AEP) to stimuli of different intensities were investigated. Sixteen normal male volunteers received ethanol, 0.8 ml/kg, 100 mg meperidine, and a placebo on different days in a double-blind study. AEPs were recorded from Fz, Cz and Pz electrode placements. The stimuli were 500 msec 1000 Hz tones at 50, 60, 70 and 80 dB sound pressure level presented in a pseudo-random sequence. Meperidine had no significant effect on AEP variables. Ethanol reduced AEP activity between 24 and 250 msec but had no effect on the sustained potential measured between 300 and 450 msec.

Abstract

Seventeen normal volunteers received either 0.5 mg, 1.5 mg, or 2.5 mg physostigmine i.v. in a placebo-drug-placebo single-blind design. EEG was recorded simultaneously and analyzed by computerized spectral analysis. Eleven healthy elderly volunteers (mean age = 69.1 years) with mild memory impairment were treated with placebo, followed by oral choline chloride (either 8 g/day for 3 weeks, or 16 g/day for 1 week), and then, again, placebo. Recordings of spontaneous EEG and EEG event-related potentials (contingent negative variation) were obtained during both placebo and choline treatments. The larger doses of physostigmine produced an increase in low frequency activity and a slowing of the peak alpha frequency. Oral choline chloride had no effect on the EEG as measured by spectral analysis, but appears to have differential effects on contingent negative variation (CNV) amplitude and reaction time, depending upon the initial CNV amplitude.

Abstract

The rationale for the use of vasodilators in the aged has changed from the attempt to increase cerebral blood flow to the attempt to improve cerebral metabolism. Review of 102 studies of eight vasodilators showed that significantly more controlled studies claimed practical clinical benefit from drugs supposed to improve neuronal intermediary metabolism with secondary vasodilatation than from drugs supposed to have only vasodilator action (P less than .005). Studies of both classes of drugs often suffered from poor study design, inappropriate and inconsistent application of outcome measurements, as well as negative bias due to selection of severely demented subjects. Future studies should be placebo-controlled investigations of drugs with primarily metabolic action, address questions of dose and time response, consistently use appropriate outcome measurement, and concentrate on the elderly in whom cognitive improvement is possible.

Abstract

Eight elderly patients with mild memory impairment were given choline chloride, a drug that increases brain acetylcholine concentrations. After 16 g/day of choline for 7 days, average memory performance was not different from performance during pre- and postcholine placebo treatment, although the patient with the poorest baseline performance improved considerably on choline.

Abstract

Beta-endorphin, morphine, and saline were given intravenously to a single schizophrenic subject on separate occasions in a double-blind design. EEG spectral analyses performed on data collected before and after drug injection demonstrated that beta-endorphin and morphine produced similar increases in alpha power within 5 to 15 minutes after injection. This effect could be distinguished from two placebo (saline) injections. These data suggest that intravenous beta-endorphin can produce changes in the central nervous system in humans.

Abstract

Nineteen normal male subjects received 1.0 milligram of physostigmine or 1.0 milligram of saline by a slow intravenous infusion on two nonconsecutive days. Physostigmine significantly enhanced storage of information into long-term memory. Retrieval of information from long-term memory was also improved. Short-term memory processes were not significantly altered by physostigmine.

Abstract

In controlled experiments rhesus monkeys that had received phenylethylamine (PEA) demonstrated behavior similar to that reported after the administration of amphetamines, except that tolerance to PEA did not develop. These findings are of psychiatric interest because PEA is found in the human body and is a specific substrate for type B MAO, which is found in decreased quantities in certain schizophrenic patients.

Abstract

Sixteen college-educated male subjects were given an object description task during placebo conditions and while intoxicated with marijuana extract cookies calibrated to 0.3 mg/kg delta-9-tetrahydrocannabinol, a dose within the range of usual social use. The task was scored for fluency, flexibility, elaboration, and uniqueness, all of which represent associational thinking and are considered to be components of creativity. Marijuana did not enhance any of these measures.

Abstract

Twelve male college students received orally on different days NIMH marijuana extract calibrated to contain 0.7 mg/kg delta-9-tetrahydrocannabinol, 1.0 ml/kg 95% ethanol, and placebo in a double-blind balanced-order design. The contingent negative variation (CNV), auditory evoked potential (EP), heart rate (HR), and subjective measures of intoxication were recorded prior to drug ingestion and at regular intervals for 4.5 h postdrug. Both drugs produced significant subjective effects. Marijuana increased HR but did not have a significant effect on CNV amplitude or EP peak amplitudes and latencies. Ethanol increased HR, but not significantly, and reduced CNV amplitude and N1-P2 amplitude. Time-action curves for ethanol's effect on subjective high, HR, and N1-P2 amplitude were parallel, peaking between 0.5 and 1.5 h postdrug and returning to baseline by the end of testing. Time-action curve for ethanol's effect on the CNV showed continuing amplitude reduction throughout the test session.

Abstract

Three cognitive tasks in which performance depends primarily on the rate of cognitive processing were given to 24 male subjects before and after oral doses of methamphetamine (10 mg), diphenhydramine hydrochloride (100 mg), and placebo. Each subject was tested on Monday, Wednesday, and Friday of one week with drug orders balanced across subjects. Compared with placebo and diphenhydramine, methamphetamine increased the rate at which a visual display was scanned for a target stimulus. Methamphetamine affected neither a time-production task nor a divided attention task that required the subject to perform two cognitive tasks in a limited amount of time. This suggests that methamphetamine can increase cognitive processing speed on tasks involving familiar cognitive operations but that an increase is not likely in tasks involving more complicated decision processes. Compared with placebo and methamphetamine, diphenhydramine caused subjects no experience geophysical time as passing more slowly, but the drug had no significant effects on the visual search or divided-attention tasks. This suggests that time perception is more likely to be altered by diphenhydramine than is performance on tasks requiring short periods of rapid cognitive processing.

Abstract

Hospitalized alcoholics taking disulfiram were found to process information in short-term memory at a slower rate than hospitalized controls, although short-term memory capacity was similar in the two groups.

Abstract

The ability of 16 college-educated male subjects to recall from long-term memory a series of common facts was tested during intoxication with marijuana extract calibrated to 0.3 mg/kg delta-9-tetrahydrocannabinol and during placebo conditions. The subjects' ability to assess their memory capabilities was then determined by measuring how certain they were about the accuracy of their recall performance and by having them predict their performance on a subsequent recognition test involving the same recall items. Marijuana had no effect on recall or recognition performance. These results do not support the view that marijuana provides access to facts in long-term storage which are inaccessible during non-intoxication. During both marijuana and placebo conditions, subjects could accurately predict their recognition memory performance. Hence, marijuana did not alter the subjects' ability to accurately assess what information resides in long-term memory even though they did not have complete access to that information.

Abstract

Sixteen college-educated male subjects were tested on free-recall lists during intoxication with marijuana extract calibrated to 0.3 mg/kg delta-9-tetrahydrocannabinol and during placebo conditions. On each testing day subjects studied six lists using a regular overt rehearsal procedure and six lists using an association-overt rehearsal procedure in which they were to rehearse alound both list items and associations to those items. Both marijuana and the association-rehearsal procedure reduced the number of correct recalls and increased the number of intrusions (nonlist items which were incorrectly recalled as having been on the list to be learned). The intrusions were divided into three categories: a) words found on prior lists; b) associates spoken during the rehearsal; or c) totally new works not previously mentioned. Marijuana significantly increased the number of new intrusions; the association-rehearsal procedure did not. This result suggests that one of the effects of marijuana on cognitive functions in humans is to increase the number of intrusive thoughts and this may be the mechanism involved in some of the thought disorder observed with marijuana intoxication.

Abstract

Twelve men performed the Sternberg memory retrieval task under three experimental conditions: after oral doses of marihuana extract calibrated to contain 0.7 mg/kg delta9-tetrahydrocannabinol (THC), 1.0 ml/kg 95% ethanol, or placebo. Simultaneously, the EEG was recorded from Ca to linked ears and the EOG from leads above and below the right eye. In this task, subjects saw a set of 1 to 4 digits follwed by a warning tone that was followed 1.5 sec later by a test digit. Subjects indicated by pressing one of two buttons whether the test digit was in-set or out-of-the-set. There were no drug effects on N1 in the evoked potential to the warning tone, but P3 amplitude was smaller under THC and ethanol than under placebo. CNV amplitude in the interval between the warning tone and the test digit showed no drug effects, indicating that the subject was equally prepared for the test digit regardless of drug received. However, the latency of 50% resolution of the CNV was longer under THC than under placebo. THC also increased the reaction time for each set size by about 75 msec above the values for ethanol and placebo, the latter two not differing significantly. Set size affected N1 and P3 amplitudes and latencies and CNV amplitude, as well as 50% CNV resolution latency and reaction time, but there were no drug chi set size interactions.

Abstract

Auditory evoked potentials (AEPs) to tone pips at three monopolar scalters were systematically varied: tone intensity (3.0, 1.5 and 0.75 sec), and direction of attention. Interstimulus intervals were computed separately for the 9 different combinations of the three possible first prior intervals (intervals between the test stimulus and the stimulus immediately preceding it) and the three possible second prior intervals (intervals between the stimulus preceding the test stimulus and the stimulus prior to that). Our results show that temporal amplitude recovery of N1 and P2 can be based solely on the first prior interval had not effect on amplitude. Furthermore, they show that it is inadvisable to use combined N1-P2 amplitude measures since the two peaks appear to be governed by separate processes. Recovery for N1 was different from that of P2, N1 showed no intensity effects while P2 did, and N1 and P2 had different topographic distributions. Directing attention to the tones did not affect N1 or P2 amplitudes but caused a highly significant increase in both N1 and P2 latency. Attention to the tones also produced a frontal negative baseline shift following them.

Abstract

Performance on a time production task, heart rate, and subjective responses were studied in twelve male sujects given oral doses of marijuana (0.7 mg of delta-9-tetrahydrocannabinol/kg), ethanol (1.0 ml/kg), and placebo, on three testing days which were each separated by 1 week. Orders were balanced across subjects and testing conditions were double-blind. Compared to ethanol and placebo, marijuana induced a significant under-production of time intervals, suggesting an acceleration of the internal rate of time perception. The onset of this acceleration of time sense in which geophysical time seemed to pass slowly corresponded with the characteristic increase in heart rate and the onset of the subjective feelings of drug effects. Initial phases of alcohol intoxication were associated with the opposite effects on the time production task. These findings replicate previous work and indicate that an easily administered time production task provides a consistent, non-motor measure of acute marijuana intoxication and also reflects ethanol intoxication.

Abstract

Evoked potentials were recorded from the human scalp during performance of a memory retrieval task modeled after a paradigm originated by Sternberg (1966). Subjects were required to decide whether a probe digit was contained in a series of one to four target digits presented a few seconds before. The amplitude of the contingent negative variation (CNV) preceding the probe digit and the speed of CNV resolution after the probe varied as a function of target set size. CNV amplitude was greatest when the set size was one. The smaller the set size, the more positive the evoked potential 300 msec after the probe, regardless of whether a motor response was required.

Abstract

In a double-blind study, 72 normal male subjects were given either placebo or marihuana containing 20 mg. Delta-9-tetrahydrocannabinol. Stories written to cards selected from the Thematic Apperception Test did not differ on hostile or sexual content scales between drug and placebo conditions, but 6 out of 10 scales specifically constructed to detect marihuana effects were successful at differentiating the two conditions. Under marihuana the stories had a timeless, non-narrative quality, with greater discontinuity in thought sequence and more frequent inclusion of contradictory ideas. Novelty of content was somewhat increased by marihuana, while relation to the picture, imagery, repetition, and closure were not significantly affected.

Abstract

Contingent negative variations (CNVs) composed of 32 trials had a median subject consistency of 0.68 in retests separated from 5 min to 7 days. Hand measurement of the CNV was highly reliable with a median reliability of 0.96. Subject consistencies for the amplitudes and latencies of N1 and P2 components of a auditory evoked potential (AEP) had a median of 0.59 when 265 trials were averaged. These consistencies for N1 and P3 components had a median of 0.45 when only 16 trials were averaged. Median measurement reliabilities for the AEP were 0.92 for amplitudes and 0.66 for latencies.

Abstract

Following presentation and immediate free recall testing of 10 20-word lists, 48 Ss were divided into two groups, one of which received an oral dose of marihuana extract calibrated to 20 mg of ?(1)-THC and one of which received placebo. One hour later, all Ss were administered delayed recall, recognition, and order tests on the first set of words. Presentation of another set of 10 lists followed, and there were immediate recall and delayed recall, recognition, and order tests on these words. Performance of drug and placebo Ss did not differ significantly for any of the first delayed tests. However, the performance of drug Ss was poorer than that of placebo Ss on immediate recall, delayed recall, and delayed recognition of the second set of lists. We concluded that retrieval of information relevant to the occurrence or nonocurrence of an event was not affected by marihuana intoxication. Storage difficulties probably account for memory deficits due to the drug, and these difficulties appear to occur in the process of transferring information from short-term to long-term memory.

Abstract

High oral doses of marihuana extract, calibrated for content of 1 (-)-Delta(1)-tetrahydrocannabinol, significantly impaired the serial coordination of cognitive operations during a task that required sequential adjustments in reaching a goal. This disintegration of sequential thought is related to impaired immediate memory.